Functional alterations of the mitochondrially encoded ND4 subunit associated with Leber's hereditary optic neuropathy

FEBS Lett. 1994 Oct 3;352(3):375-9. doi: 10.1016/0014-5793(94)00971-6.


Leber's hereditary optic neuropathy (LHON) is a maternally inherited disease associated with point mutations in mitochondrial DNA. The most frequent of these mutations is the G-to-A substitution at nucleotide position 11,778 which changes an evolutionarily conserved arginine with a histidine at position 340 in subunit ND4 of NADH:ubiquinone reductase (respiratory complex I). We report that this amino acid substitution alters the affinity of complex I for the ubiquinone substrate and induces resistance towards its potent inhibitor rotenone in mitochondria of LHON patients. Such changes could reflect a substantial loss in the energy conserving function of NADH:ubiquinone reductase and thus explain the pathological effect of the ND4/11,778 mutation.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Arginine
  • Base Sequence
  • Blood Platelets / enzymology*
  • Conserved Sequence
  • DNA, Mitochondrial / blood
  • DNA, Mitochondrial / isolation & purification
  • DNA, Mitochondrial / metabolism
  • Electron Transport Complex I
  • Female
  • Histidine
  • Humans
  • Kinetics
  • Macromolecular Substances
  • Male
  • Mitochondria / enzymology*
  • Molecular Sequence Data
  • NADH, NADPH Oxidoreductases / blood
  • NADH, NADPH Oxidoreductases / genetics*
  • Optic Atrophies, Hereditary / enzymology*
  • Optic Atrophies, Hereditary / genetics*
  • Pedigree
  • Point Mutation*
  • Polymerase Chain Reaction / methods
  • Rotenone / pharmacology


  • DNA, Mitochondrial
  • Macromolecular Substances
  • Rotenone
  • Histidine
  • Arginine
  • NADH, NADPH Oxidoreductases
  • Electron Transport Complex I

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